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Blood Cells Mol Dis. 2003 Mar-Apr;30(2):177-83.

The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor.

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1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. scott.hiebert@mcmai.vanderbilt.edu

Abstract

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. The translocation fuses the DNA binding domain of AML1 to nearly all of the ETO co-repressor. ETO associates with the mSin3 and N-CoR co-repressors as well as histone deacetylases 1, 2, and 3. Although this is one of the most frequent chromosomal translocations in acute leukemia, accounting for 10-15% of the cases of acute myeloid leukemia (AML), the direct targets for transcriptional regulation that stimulate leukemogenesis are unknown. We found that AML1-ETO repressed the promoter of p14(ARF) tumor suppressor in transient transfection assays and reduced endogenous levels of p14(ARF) expression in multiple cell types. Chromatin immunoprecipitation assays demonstrated that AML1-ETO bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared to other acute myeloid leukemias. Therefore, p14(ARF) is a direct transcriptional target of AML1-ETO.

PMID:
12732181
[Indexed for MEDLINE]

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